We exploited antisense oligonucleotides (ASOs) to inhibit mutant androgen receptor (AR) RNA levels in the central nervous system and explored its therapeutic effects in the model mouse of spinal and bulbar muscular atrophy (SBMA) that harbors mutant AR gene with 97 CAGs. Intracerebroventricular ASO administration in the SBMA mice efficiently suppressed the mutant gene expression in the central nervous system, highlighting the neurotoxicity of mutant AR in motor neurons. RG108, an inhibitor of DNA methylation suppressed motor neuron degeneration in the SBMA mouse, suggesting that the mutant AR-induced hypermethylation of DNA is implicated in the pathomechanism of SBMA. Both motor neurons and skeletal muscles of the SBMA mouse showed mitochondrial dysfunction, up-regulation of oxidative stress, and activation of NFkB signaling, all of which were mitigated by a PPARgamma agonist pioglitazone, suggesting common molecular pathways in the neuro-muscular degeneration in SBMA.